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Article: The role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced induced iL-8 production in human bronchial epithelial cells

TitleThe role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced induced iL-8 production in human bronchial epithelial cells
Authors
Issue Date2012
PublisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/
Citation
Toxicological Sciences, 2012, v. 125 n. 2, p. 569-577 How to Cite?
AbstractCigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR 2A) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.
Persistent Identifierhttp://hdl.handle.net/10722/163448
ISSN
2015 Impact Factor: 3.88
2015 SCImago Journal Rankings: 1.686
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorLau, WKWen_US
dc.contributor.authorChan, SCHen_US
dc.contributor.authorLaw, ACKen_US
dc.contributor.authorIp, MSMen_US
dc.contributor.authorMak, JCWen_US
dc.date.accessioned2012-09-05T05:31:30Z-
dc.date.available2012-09-05T05:31:30Z-
dc.date.issued2012en_US
dc.identifier.citationToxicological Sciences, 2012, v. 125 n. 2, p. 569-577en_US
dc.identifier.issn1096-6080en_US
dc.identifier.urihttp://hdl.handle.net/10722/163448-
dc.description.abstractCigarette smoking is a major risk factor in chronic obstructive pulmonary disease (COPD) with chronic airway inflammation as a key feature. Blockade of serotonin receptor 2A (5-HTR 2A) with ketanserin has been found to improve lung function in COPD patients. Furthermore, ketanserin has been shown to possess anti-inflammatory properties in vivo. In this study, we investigated the antioxidative and anti-inflammatory properties of ketanserin and its underlying mechanism of action on cigarette smoke-induced interleukin (IL)-8 release in vitro. Primary normal human bronchial epithelial cells and human bronchial epithelial cell line (BEAS-2B) were treated with or without ketanserin prior to exposure to cigarette smoke medium (CSM). Exposure to CSM caused elevation of both mRNA and release of IL-8 with increased phosphorylation of p38 and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Consistently, CSM-induced IL-8 release was blocked by SB203580, U0126, or MEK1 small interfering RNA (siRNA) but not SP600125. On the other hand, CSM caused a dose-dependent decrease in the ratio of reduced glutathione to oxidized glutathione (rGSH/GSSG) together with an increased translocation of Nrf2 to the nucleus demonstrated by Western blot analysis. Knock down of Nrf2 by siRNA completely blocked CSM-induced IL-8 release. Ketanserin suppressed CSM-induced IL-8 release by inhibiting p38, ERK1/2 MAPK, and Nrf2 signaling pathways and partially inhibited CSM-induced reduction of rGSH/GSSG ratio. Our data demonstrated the novel antioxidative and anti-inflammatory role of ketanserin via the Nrf2 signaling pathway in CSM-exposed human bronchial epithelial cells. This may open up new perspectives in the development of novel therapeutic targets in the treatment of cigarette smoke-related COPD. © The Author 2011. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.en_US
dc.languageengen_US
dc.publisherOxford University Press. The Journal's web site is located at http://toxsci.oxfordjournals.org/en_US
dc.relation.ispartofToxicological Sciencesen_US
dc.titleThe role of MAPK and Nrf2 pathways in ketanserin-elicited attenuation of cigarette smoke-induced induced iL-8 production in human bronchial epithelial cellsen_US
dc.typeArticleen_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1093/toxsci/kfr305en_US
dc.identifier.pmid22048642-
dc.identifier.scopuseid_2-s2.0-84856082183en_US
dc.identifier.hkuros204399-
dc.identifier.volume125en_US
dc.identifier.issue2en_US
dc.identifier.spage569en_US
dc.identifier.epage577en_US
dc.identifier.eissn1096-0929-
dc.identifier.isiWOS:000299346000023-
dc.publisher.placeUnited Kingdomen_US

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